Bazedoxifene acetate(1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetic acid), having the chemical formula shown below:
belongs to the class of drugs typically referred to as selective estrogen receptor modulators (SERMs). Consistent with its classification, bazedoxifene demonstrates affinity for estrogen receptors (ER) but shows tissue selective estrogenic effects. For example, bazedoxifene acetate demonstrates little or no stimulation of uterine response in preclinical models of uterine stimulation. Conversely, bazedoxifene acetate demonstrates an estrogen agonist-like effect in preventing bone loss and reducing cholesterol in an ovariectomized rat model of osteopenia. In an MCF-7 cell line (human breast cancer cell line), bazedoxifene acetate behaves as an estrogen antagonist. These data demonstrate that bazedoxifene acetate is estrogenic on bone and cardiovascular lipid parameters and antiestrogenic on uterine and mammary tissue and thus has the potential for treating a number of different diseases or disease-like states wherein the estrogen receptor is involved.
U.S. Pat. Nos. 5,998,402 and 6,479,535 report the preparation of bazedoxifene acetate and characterize the salt as having a melting point of 174-178° C. The synthetic preparation of bazedoxifene acetate has also appeared in the general literature. See, for example, Miller et al., Drugs of the Future, 2002, 27(2), 117-121, which reports the salt as a crystalline solid having a melting point of 170.5-172.5° C. Further description of the drug's biological activity has appeared in the general literature as well (e.g. Miller, et al. Drugs of the Future, 2002, 27(2), 117-121; Miller et al., J. Med. Chem., 2001, 44, 1654-1657).
It is well known that the crystalline polymorph form of a particular drug is often an important determinant of the drug's ease of preparation, stability, solubility, storage stability, ease of formulation and in vivo pharmacology. Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular polymorph form. In cases where two or more polymorph substances can be produced, it is desirable to have a method to make both polymorphs in pure form. In deciding which polymorph is preferable, the numerous properties of the polymorphs must be compared and the preferred polymorph chosen based on the many physical property variables. It is entirely possible that one polymorph form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc are deemed to be critical. In other situations, a different polymorph maybe preferred for greater solubility and/or superior pharmacokinetics.
Because of the potential advantages associated with one pure polymorphic form, it is desirable to prevent or minimize polymorphic conversion (i.e., conversion of one form to another) when two or more polymorphic forms of one substance can exist. Such polymorph conversion can occur during both the preparation of formulations containing the polymorph, and during storage of a pharmaceutical dosage form containing the polymorph. Two different crystalline polymorphs of anhydrous bazedoxifene acetate, form A and form B, have been disclosed in U.S. patent application Ser. Nos. 11/100,983 and 11/100,998, both filed Apr. 6, 2005 and each of which is incorporated by reference herein in its entirety. Form A is distinguished from Form B by numerous physical properties which are tabulated below. As can be seen from the data in the Table, Form B appears to be thermodynamically more stable than form A, contributing to numerous advantages. For example, the increased stability of form B would facilitate manufacturing and purification processes. Form B would also be expected to have better resistance to degradation brought on by, for example, exposure to high temperatures and/or humidity, and have a longer shelf-life than Form A or amorphous material. In contrast, Form A appears to have higher solubility in aqueous and organic solvent systems than does form B, which is advantageous in particular formulations or doses where the solubility of the particular composition is of concern. For example, higher solubility can contribute to better biological absorption and distribution of the drug, as well as facilitate formulation in liquid carriers.
TABLEMeasurementForm AForm BMelting Point176° C.181° C.Heat of Fusion94.6 J/G108.4 J/GSolubility-Water0.49 mg/mL0.23 mg/mLSolubility-Org24.5 mg/mL12.4 mg/mL(EtOH/EtOAc/Tol)Intrinsic Dissolution0.125 mg/cm2-min0.09 mg/cm2-minRateDSCSingle MeltingSingle MeltingEndothermEndotherm176.1° C.181.1° C.TGASimilarSimilarX-Ray Powder12.7°, 16.0°, 18.5°, 20.7°,13.3°, 20.8°, 21.6°,22.3° (2θ)25.0° (2θ)Raman/IR1511, 1467 cm−11513, 1449, 1406 cm−1
Given the potential advantages of a single polymorphic form, it can be seen that formulations having reduced polymorphic conversion can provides significant benefits. The bazedoxifene acetate formulations and compositions described herein helps meet these and other needs.